Sex Determines Cardiovascular Hemodynamics in Hypertension

ORIGINAL ARTICLE Sex determines cardiovascular hemodynamics in hypertension

P Krzesiński, A Stańczyk, G Gielerak, B Uziębło-Życzkowska, M Kurpaska, K Piotrowicz and A Skrobowski

The aim of this study was to evaluate the inﬂuence of sex on cardiovascular hemodynamics and heart remodeling in 144 patients with arterial hypertension that underwent: (1) echocardiography (that is, indices of left ventricular diastolic function: e′, E/e′), (2) impedance cardiography (that is, systemic vascular resistance (SVR), total artery compliance (TAC) and Heather index (HI)) and (3) applanation tonometry (augmentation index (AI), central systolic and diastolic blood pressure (CSBP, CDBP), central pulse pressure (CPP)). Women, in comparison with men, revealed to have: (1) stiffer arteries—lower TAC (1.93 ± 0.55 vs 2.16 ± 0.59 ml per mm Hg; P = 0.025), higher CSBP (128.7 ± 14.9 vs 123.4 ± 13.2 mm Hg; P = 0.036), CPP (39.9 ± 9.5 vs 33.8 ± 9.0 mm Hg; P = 0.0002), AI (31.5 ± 8.7 vs 17.5 ± 12.7%; Po0.00001), SVR (1257.6 ± 305.6 vs 1091.2 ± 240.7 dyn × s × cm−5; P = 0.002) and (2) higher left ventricular performance—HI (16.3 ± 4.3 vs 11.7 ± 3.2 Ohm × s2; Po0.00001). In women CSBP, CPP and AI were more clearly associated with left ventricular ﬁlling pressure (e′)(r = − 0.39, r = − 0.45, r = − 0.44, Po0.01; respectively). These relations were remarkably weaker in men. Hypertensive women characterized with lower large artery compliance, more pronounced augmentation of central blood pressure and more distinctive association of central blood pressure with left ventricular diastolic function. Sex differences in cardiovascular function can impact the individualized management of arterial hypertension.

Journal of Human Hypertension (2015) 29, 610–617; doi:10.1038/jhh.2014.134; published online 29 January 2015

INTRODUCTION differences in the mechanisms of cardiovascular dysfunction and Arterial hypertension (AH) is the main modifiable risk factor of remodeling in hypertensive males and females that can be cardiovascular diseases. Young adult women have lower blood depicted by these methods. pressure (BP) than men, whereas, after the fifth decade of life, the prevalence of AH in females increases rapidly. It results in the PATIENTS AND METHODS acceleration of cardiovascular remodeling and steeper increase of cardiovascular risk.1–4 It can be explained by the change of female Study population This study included patients with at least 3-month history of AH defined hormonal status and the loss of cardiovascular protection 1 provided by estrogens in premenopausal women.4–6 In addition, according to the European Society of Cardiology guidelines. Exclusion criteria comprised: (1) confirmed secondary AH, (2) AH treated with three hypertensive females, even in the absence of large coronary or more medicines before recruitment, (3) heart failure, (4) cardiomyo- artery disease and left ventricular systolic dysfunction, tend to pathy, (5) significant heart rhythm disorders, (6) significant valvular disease, experience more symptoms related to AH, including impaired (7) kidney failure (GFR below 60 ml min− 1 per 1.73 m2), (8) chronic exercise tolerance and chest pain.6 Although women with AH are obstructive pulmonary disease, (9) diabetes, (10) polyneuropathy, more aware of the need of treatment and visit physicians more (11) peripheral vascular disease, (12) ageo18 years and 465 years. The frequently2 they do not reach satisfactory control of BP.3 The subjects treated with hypotensive drugs were recommended to discon- question whether, and how, the antihypertensive therapy should tinue taking them 7 days before the examination. The group selected to the analysis comprised patients from clinical be sex-adjusted remains without satisfactory answer. study, registered at ClinicalTrials.gov—NCT01996085. The study was Several studies reported sex differences in cardiovascular conducted according to Good Clinical Practice guidelines and the function in patients with AH. They revealed that premenopausal Declaration of Helsinki, with the approval of local ethics committee (no women were characterized with relatively higher vascular 21/WIM/2011). Each patient provided written informed consent to stiffness, better left ventricular performance and different patterns participate in the study. of modulation by the autonomic nervous system.5,7,8 However, the The clinical examination was performed in the morning hours with knowledge about the mechanisms underlying the different consideration of cardiovascular risk factors and symptoms indicating secondary cause of AH.1 The office blood pressure measurement was patterns of ‘hypertensive disease’ in males and females is still fi performed automatically (Omron M4 Plus, Japan) by a technique compliant de cient. Especially the sex-related differences in relations with the European Society of Cardiology guidelines.1 The average value of between those parameters are poorly known. Thus, the need for the two measurements was used as the final reading. studies providing comprehensive picture of complex nature of interaction between heart and vessels still exists. Echocardiography The aim of our study was to evaluate the influence of sex on Two-dimensional echocardiography was performed using standard para- cardiovascular hemodynamics, heart structure and function. We sternal, apical and subcostal views (2.5 MHz transducer; VIVID S6 GE used three noninvasive techniques to provide combined hemo- Medical System, Wauwatosa, WI, USA). The dimension of the left atrium, dynamic assessment—echocardiography, applanation tonometry left ventricular end diastolic diameter and interventricular septum and impedance cardiography. We hypothesize that there are diameter were measured in the parasternal long-axis view in late diastole

Department of Cardiology and Internal Diseases, Military Institute of Medicine, Warsaw, Poland. Correspondence: Dr P Krzesiński, Department of Cardiology and Internal Diseases, Military Institute of Medicine, Szaserów Street 128, 04-141 Warsaw 44, Poland. E-mail: [email protected] Received 15 October 2014; accepted 11 December 2014; published online 29 January 2015 Sex and hemodynamics in hypertension P Krzesiński et al 611 of left atrium and left ventricle (LV), respectively. Left atrium area was Applanation tonometry calculated from apical four-chamber view. Left ventricular ejection fraction Assessment of central blood pressure (CBP) and augmentation index (AI) was calculated according to the Simpson’s formula using a two- was performed noninvasively using the SphygmoCor system (AtCor dimensional image of the LV chamber during systole and diastole in the Medical Inc Pty Ltd, Sydney, NSW, Australia). Radial artery pressure four- and two-chamber apical views. waveforms were recorded at the left wrist, using applanation tonometry The left ventricular hypertrophy (LVH) was diagnosed according to the with a high-fidelity micromanometer (Millar Instruments, Houston, ASE-recommended formula for the estimation of left ventricular mass TX, USA). The arterial pulse waves were processed by the SphygmoCor index (LVMI) from two-dimensional linear LV measurements and indexed software (version 9.0; AtCor Medical Inc Pty Ltd) and the corresponding 4 − 2 to body surface area (BSA, cutoff values for men LVMI 115 g m , for aortic pressure waveform was generated from the radial artery waveform 4 − 2 women 95 g m ). using a validated transfer function with identification of inflection fl Mitral valve in ow was recorded in the apical four-chamber view with point resulting from the wave reflection and the incisura resulting from pulsed wave Doppler gate positioned in the LV on the level of the mitral the aortic valve closure.11 Augmentation pressure (AP (mm Hg)) was valve edges. The following parameters were measured: E/A ratio and phase calculated by the maximum systolic pressure minus pressure at the fi E deceleration time (EdecT). The apical ve-chamber view enabled inflection point. Only high-quality recordings (quality index of 480%) fl simultaneous registration of the ow pattern through aortic and mitral were included in the analysis. The measurements were performed in the valves and isovolumic diastolic time calculation. Tissue Doppler imaging supine position just after examination by ICG. The radial pulse and was performed in the apical views to acquire mitral annular velocity. The transferred aortic blood pulse were calibrated against the last measure- sample volume was positioned at 1 cm within the septal insertion sites of ment of brachial systolic BP (SBP) and diastolic BP (DBP) by oscillometric the mitral leaflets and adjusted as necessary (usually 5–10 mm) to cover module of the Niccomo device. The following parameters were included the longitudinal excursion of the mitral annulus in diastole. In addition, in the analysis: central systolic blood pressure (CSBP (mm Hg)), mitral septal annulus early diastolic velocity (e′) was measured and E/e′ central diastolic blood pressure (CDBP (mm Hg)), central pulse pressure ratio was calculated. The diagnosis of left ventricular diastolic dysfunction (CPP (mm Hg)) and AI. was based on the current guidelines.9,10 Following values were considered abnormal: e′o8cms− 1; left atrium 440 mm for men and 438 mm for women; E/Ao0.8, EdecT4200 ms, isovolumic relaxation time ⩾ 100 ms, Statistical analysis E/e′ ratio 48. The statistical analysis was performed using Statistica 7.0 (StatSoft, Inc., Tulsa, OK, USA). The distribution and normality of the data were assessed by visual inspection and the Kolmogorov–Smirnov test. Continuous Impedance cardiography variables were presented as means ± s.d. and categorical variables as All impedance cardiography (ICG) measurements were performed using absolute and relative frequencies (percentages). The comparison of the the Niccomo device (Medis, Ilmenau, Germany) after 10 min of rest in a absolute values between men and women was performed with the use of supine position. Data were recorded during a 10-min assessment and Student's t-test for normally distributed data and Mann–Whitney U-test as exported to the dedicated software (Niccomo Software). The final analysis a nonparametric alternative. The association between chosen indices of included mean values of hemodynamic parameters, such as: basic cardiovascular function or structure was investigated with Pearson’s impedance (Z0 (Ohm)), the amplitude of the systolic wave of the ICG (Spearman’s) correlation coefficients. AP-value of o0.05 was taken to fl − 1 (dZmax); thoracic uid content (TFC (1 × kOhm )), calculated from Z0 as its indicate statistical significance. − 1 − 2 converse: TFC = 1000/Z0, and its index to BSA (TFCI (1 × kOhm ×m )); dZmax—maximum amplitude of ICG wave; stroke volume (SV (ml)); calculated using the Sramek and Bernstein formula SV = VEPT × RESULTS (dZmax/Z0) × LVET, accounting for weight, height and sex (variable VEPT), − 2 The study group involving 144 patients (99 men) was dZmax and left ventricular ejection time (LVET), and its index (SI (ml × m )); cardiac output (CO (l × x min − 1)), calculated as CO = SV × HR (heart rate), characterized in Table 1. The female subgroup was dominated − 2 − 1 by premenopausal women (n = 29, 64.4%). None of the and its index (CI l × m × min ); acceleration time index (ACI (100 × Z0- ×s− 2)), stating for maximum acceleration of blood flow between aortic women received hormonal replacement therapy. There was no valve opening and the time of dZmax–ACI = 100 × dZmax/dt; velocity index difference between subgroups with respect to age, SBP, DBP, − 1 2 (VI (1000 × Z0 ×s )): VI = 1000 × dZmax/Z0; Heather index (HI (Ohm × s )): HR, GFR, BMI. HI = dZmax × TRC, a derivate of TRC (the time interval between the R-peak of the ECG and C-point of ICG wave) characterizing the maximum The differences between men and women contraction force of the left ventricle and corresponding to cardiac inotropism; systemic vascular resistance (SVR (dyn × s × cm − 5)): SVR = 80 × Echocardiography. In the echocardiographic assessment, (MBP − CVP)/CO, where CVP is the central venous pressure (assumed the only differences which we identified were left chambers value 6 mm Hg) and its index (SVRI (dyn × s × cm − 5 ×m2)); total arterial dimensions and LVMI, reflecting constitutional differences compliance (TAC (ml × mm Hg − 1)): TAC = SV/PP. between sexes—Table 2. There was no statistically significant

Table 1. Basic characteristics of the study group

Males (n = 99) Females (n = 45) P Study group (n = 144)

Age (years), mean ± s.d. 44.6 ± 10.9 46.6 ± 9.2 0.284 45.2 ± 10.4 HR (b.p.m.), mean ± s.d. 74.2 ± 10.9 72.3 ± 10.3 0.331 73.6 ± 10.7 SBP (mm Hg), mean ± s.d. 141.6 ± 11.9 140.3 ± 15.2 0.575 141.2 ± 13.0 DBP (mm Hg), mean ± s.d. 91.0 ± 9.0 89.0 ± 9.9 0.242 90.3 ± 9.3 Mild AH, n (%) 78 (79.8) 37 (82.2) 0.711 115 (79.9) Moderate AH, n (%) 20 (20.2) 8 (17.8) 0.733 28 (19.4) Severe AH, n (%) 1 (1.0) 0 (0.0) 0.137 1 (0.7) Previous hypotensive treatment, n (%) 20 (20.2) 8 (17.8) 0.733 28 (19.4) BMI (kg m − 2), mean ± s.d. 29.4 ± 3.7 28.3 ± 5.1 0.150 29.0 ± 4.2 GFR (ml min per 1.73 m2), mean ± s.d. 98.2 ± 18.5 102.2 ± 18.8 0.177 99.8 ± 18.7 Abbreviations: AH, arterial hypertension; BMI, body mass index; DBP, diastolic blood pressure; GFR, glomerular ﬁltration rate; HR, heart rate; SBP, systolic blood pressure.

© 2015 Macmillan Publishers Limited Journal of Human Hypertension (2015) 610 – 617 Sex and hemodynamics in hypertension P Krzesiński et al 612 influence of sex on left ventricular ejection fraction and absolute CPP and AI were distinctly associated with left ventricular filling values of the parameters characterizing left ventricular diastolic pressure (e′) and E/e′—Figure 1. These relations were remarkably dysfunction. weaker in men. On the other hand, the association of E/A ratio with central hemodynamics was more pronounced than in Applanation tonometry and impedance cardiography. Brachial BP women. CPP and AI revealed to be associated with HR to the was comparable for both sexes—Table 3. Women revealed to same extent in women and men. The significant differences have higher CSBP, CPP and AI and significantly lower peripheral appeared in relation between central blood pressure and amplification (brachial to central differences in SBP and PP). impedance parameters characterizing afterload. In women, it Males characterized with higher SV, CO and lower SVR but the was both SVR and TAC that were associated with CDBP (and TAC values of those parameters normalized to body size (SI, CI and additionally with CPP). In men, only SVR was associated with SVRI, respectively) were comparable—Table 4. The female arterial central hemodynamics evaluated by applanation tonometry (no tree revealed to be less compliant (lower TAC and higher SVR) and correlation with TAC was revealed). the parameters characterizing left ventricular function as a blood pump derived from dZ (ACI, VI, HI) were higher. The significant max DISCUSSION sex difference in TFC (and Z0 as its inverse) was eliminated after indexing to BSA. The results of our study revealed sex differences in some crucial hemodynamic parameters and dissimilarities in the interactions Interrelations between characteristics of heart and vessels. The between central hemodynamics, left ventricle and peripheral influence of age on CPP and AI was slightly more pronounced in arterial tree. The strength of our analysis is the combined women—Table 5. Both CPP and AI were associated with LVMI hemodynamic assessment with the use of complementary (irrespective of sex). Some sex differences appeared in the relation noninvasive methods. This approach provided a complex picture of central hemodynamics with diastolic function. In women, CSBP, of cardiovascular hemodynamics in men and women pointing some sex differences in pathophysiology of arterial hypertension. Our study subgroups revealed to be comparable with respect to basic characteristics that eliminated the potential bias of age, BP, Table 2. The comparison of males and females in echocardiography HR and renal function.

Males (n = 99) Females (n = 45) P Sex differences in absolute values of the measured parameters LVH, n (%) 7 (7.1) 8 (17.8) 0.051 In our study, the most pronounced sex differences were LVDdf, n (%) 24 (25.3) 10 (23.3) 0.800 observed for central hemodynamics. We confirmed the previous LA enlargement, n (%) 19 (19.2) 4 (8.9) 0.112 observations that women, having comparable brachial BP, — LV enlargement, n (%) 0 (0.0) 0 (0.0) characterized with higher CBP than men.3,12,13 The differences IVSD (mm), mean ± s.d. 10.3 ± 1.0 9.5 ± 1.1 0.00006 ± ± ± o concerned CSBP and CPP, whereas CDBP was not influenced LVEDD (mm), mean s.d. 49.9 3.2 46.0 3.4 0.00001 fi LA (mm), mean ± s.d. 37.9 ± 2.7 34.5 ± 3.2 0.0001 by sex. Peripheral ampli cation of systolic BP and PP in women, LAA (cm2), mean ± s.d. 19.3 ± 3.3 17.0 ± 2.4 0.005 expressed as brachial to central difference, was almost half LVMI (g m −2), mean ± s.d. 90.9 ± 15.0 84.0 ± 15.7 0.015 of this reported in men. Of special importance is prominently LVEF (%), mean ± s.d. 64.9 ± 3.2 65.8 ± 3.1 0.115 higher AI, in females twice as high as in males. Ferrario et al.3 IVRT (ms), mean ± s.d. 97.5 19.5 98.6 ± 16.2 0.600 evaluated the hemodynamic and hormonal status of 39 women ± ± ± E/A, mean s.d. 1.09 0.36 1.04 0.30 0.473 and 61 men with AH (mean age of 53 ± 1 years) and revealed EdecT (ms), mean ± s.d. 191.2 ± 50.0 184.1 ± 41.1 0.558 e′ (cm s − 1), mean ± s.d. 9.75 ± 2.62 9.5 ± 2.62 0.669 higher values of arterial stiffness indices (PP, SVR, AI and pulse E/e′, mean ± s.d. 7.0 ± 1.54 7.5 ± 1.90 0.075 wave velocity) in women than in men. Lower blood pressure amplification in women was also reported in older population Abbreviations: EdecT, phase E deceleration time; e′, mitral septal annulus (58 ± 10 years).12 early diastolic velocity; IVRT, isovolumic relaxation time; IVSD, interven- Increased CPP and AI in women are mainly explained by lower tricular septum diameter; LA, left atrium; LAA, left atrium area; LVDdf, left body size. Shorter distance of wave propagation results in earlier ventricular diastolic dysfunction; LVEDD, left ventricular end diastolic reflection from peripheral vascular bed and, as a consequence, diameter; LVEF, left ventricular ejection fraction; LVH, left ventricular 14 hypertrophy; LVMI, left ventricular mass index. early systolic wave return to the heart. However, in the study of Berry et al.15 elderly hypertensive women had lower arterial

Table 3. The comparison of males and females in applanation tonometry

Males (n = 99) Females (n = 45) P

Brachial SBP (mm Hg), mean ± s.d. 136.2 ± 13.6 136.2 ± 15.3 0.999 Brachial DBP (mm Hg), mean ± s.d. 88.6 ± 8.9 87.8 ± 9.8 0.609 Brachial PP (mm Hg), mean ± s.d. 47.6 ± 10.1 48.4 ± 10.1 0.635 CSBP (mm Hg), mean ± s.d. 123.4 ± 13.2 128.7 ± 14.9 0.036 CDBP (mm Hg), mean ± s.d. 89.9 ± 9.1 88.8 ± 10.1 0.591 CPP (mm Hg), mean ± s.d. 33.8 ± 9.0 39.9 ± 9.5 0.0002 AI (%), mean ± s.d. 17.5 ± 12.7 31.5 ± 8.7 o0.00001 Brachial to central SBP difference (mm Hg), mean ± s.d. 12.8 ± 4.7 7.6 ± 3.3 o0.00001 Brachial to central DBP difference (mm Hg), mean ± s.d. − 1.1 ± 0.6 − 1.0 ± 0.5 0.779 Brachial to central PP difference (mm Hg), mean ± s.d. 13.8 ± 4.7 8.6 ± 3.3 o0.00001 Abbreviations: AI, augmentation index; CDBP, central diastolic blood pressure; CPP, central pulse pressure; CSBP, central systolic blood pressure; DBP, diastolic blood pressure; PP, pulse pressure; SBP, systolic blood pressure.

Table 4. The comparison of males and females in impedance cardiography

Males (n = 99) Females (n = 45) P

SV (ml), mean ± s.d. 103.1 ± 26.0 89.8 ± 24.6 0.004 SI (ml × m − 2), mean ± s.d. 48.7 ± 10.9 51.4 ± 13.4 0.322 CO (l × m − 2), mean ± s.d. 7.39 ± 155 6.31 ± 1.36 0.00006 CI (l × m − 2 × min − 1), mean ± s.d. 3.50 ± 0.68 3.49 ± 0.62 0.611 HR (b.p.m.), mean ± s.d. 73.2 ± 10.7 70.9 ± 10.2 0.220 VI (1000 × Ohm × s − 1), mean ± s.d. 45.6 ± 13.0 52.8 ± 13.8 0.003 ACI (100 × Ohm × s − 2), mean ± s.d. 68.8 ± 27.6 80.2 ± 33.5 0.054 HI (Ohm × s2), mean ± s.d. 11.7 ± 3.2 16.3 ± 4.3 o0.00001 SVR (dyn × s × cm − 5), mean ± s.d. 1091.2 ± 240.7 1257.6 ± 305.6 0.002 SVRI (dyn × s × cm − 5 m2), mean ± s.d. 2287.1 ± 451.4 2240.0 ± 494.9 0.253 TAC (ml × mm Hg − 1), mean ± s.d. 2.16 ± 0.59 1.93 ± 0.55 0.025 Z0 (Ohm), mean ± s.d. 33.3 ± 3.9 38.9 ± 4.7 o0.00001 dZmax (Ohm), mean ± s.d. 1.50 ± 0.38 2.03 ± 0.48 o0.00001 TFC (1 × kOhm − 1), mean ± s.d. 30.4 ± 3.8 26.0 ± 3.1 o0.00001 TFCI (1 × kOhm − 1 ×m− 2), mean ± s.d. 14.5 ± 2.3 14.6 ± 2.3 0.771

Abbreviations: ACI, acceleration time index; CO, cardiac output; CI, cardiac index; dZmax, maximum amplitude of ICG wave; HI, Heather index; HR, heart rate; SI, stroke index; SV, stroke volume; SVR, systemic vascular resistance; SVRI, systemic vascular resistance index; TAC, total arterial compliance; TFC, thoracic ﬂuid content; TFCI, thoracic ﬂuid content index; VI, velocity index; Z0, basic impedance.

Table 5. The relations between age, heart and vessels characteristics in males and females

Vs CSBP Vs CDBP Vs CPP Vs AI

Males Females Males Females Males Females Males Females

Age 0.28** 0.10 0.04 − 0.21 0.30** 0.37* 0.44# 0.52#

Echocardiographic parameters LVMI 0.26* 0.42** − 0.01 0.28 0.43# 0.47** 0.37# 0.31** LVEF 0.05 0.06 0.01 0.16 0.01 − 0.11 0.01 0.05 e′ − 0.24* − 0.39** − 0.23* 0.20 − 0.06 − 0.45** − 0.21* − 0.44** E/e′ 0.09 0.21 0.12 0.05 0.01 0.35* 0.08 0.30* E/A − 0.32** − 0.37** − 0.24* 0.16 − 0.18 − 0.28 − 0.38# − 0.17

ICG parameters HR − 0.01 0.01 − 0.34** − 0.29* − 0.36# − 0.35* − 0.35# − 0.35# SV 0.15 0.08 − 0.04 − 0.18 0.25 0.30* 0.12 0.19 CO 0.16 0.01 0.16 − 0.20 0.03 0.21 − 0.10 − 0.05 SVR 0.26** 0.27 0.31** 0.47** 0.10 − 0.08 0.24* 0.10 TAC − 0.15 − 0.41** − 0.07 − 0.35** − 0.17 − 0.31* 0.03 − 0.06 dZmax − 0.12 0.10 − 0.21* − 0.07 0.05 0.24 − 0.03 −0.04 Abbreviations: AI, augmentation index; CDBP, central diastolic blood pressure; CPP, central pulse pressure; CSBP, central systolic blood pressure; CO, cardiac output; dZmax, maximum amplitude of ICG wave; e′, mitral septal annulus early diastolic velocity; HR, heart rate; ICG, impedance cardiography; LVEF, left ventricular ejection fraction; LVMI, left ventricular mass index; SV, stroke volume; SVR, systemic vascular resistance; TAC, total arterial compliance. *Po0.05; **Po0.01; #Po0.001.

compliance even after adjustment for aortic area and Segers Interesting observations were provided by the analysis of dZmax et al.16 proved that higher AI in females was independent of and its derivatives (VI, HI, ACI). Females revealed higher values of differences in height and systolic duration. these parameters, which characterize LV function as a ‘blood Impedance cardiography revealed that women characterized pump’. The difference was the most pronounced for HI, which is with lower SV, CO and higher SVR than men. However, after the indicator of heart inotropic state including the component of adjustment to BSA, the indexed values were comparable. Similar blood volume. observations were previously reported.3,7 The importance of SV Better LV performance was also suggested by more dynamic was not shown in direct comparison but revealed in the blood ejection (featured by VI and ACI). Segers et al.16 reported evaluation of arterial compliance. Lower absolute amount of that in healthy young and middle-aged subjects, forward wave ejected blood was related with higher PP and resulted in lower (dZmax) has relevant magnitude in determining CPP. This TAC. This observation suggests higher stiffness of female aorta. In observation may partly explain our results. young and middle-aged women it is supposed to be more Sex differences in thoracic impedance (Z0) and TFC (the 17,18 functional state than structural remodeling because female heart converse of Z0) that we observed were previously presented. is forced to interact with narrowed and shorter blood vessels and It is mainly the effect of smaller female thoracic cross-sectional adapt to higher pulsatility.3,14 Thus, blood volume ejected from LV area, size of the heart and vessels and relatively higher fat tissue during systole (SV) faces functionally stiffer vessel tube and component.18 Indexing TFC to BSA (TFCI) limits this bias and generates higher pressure on the aortic wall. simpliﬁes the approach to its interpretation.

Figure 1. The correlation plots for chosen hemodynamic parameters: AI (%) vs e′; CPP (mm Hg) vs e′; CSBP (mm Hg) vs TAC (ml mm Hg − 1). Left charts—women, right charts—men. AI, augmentation index; CPP, central pulse pressure; CSBP, central systolic blood pressure; TAC, total arterial compliance.

Echocardiographic assessment in our group did not reveal the shortening), but those differences tended to disappear after differences of statistical signiﬁcance in LV systolic performance. menopause. Gerdts et al.20 revealed higher left ventricular ejection However, several studies have reported better LV function fraction, endocardial and midwall fractional shortening and lower evaluated by echocardiography in hypertensive women than in end-systolic wall stress in hypertensive women with LVH. men.19–22 Already 25 years ago Garavaglia et al.22 observed better The echocardiographic assessment of sex differences in heart echocardiographic left ventricular indices in females (including left chamber dimensions and absolute left ventricular mass are ventricular ejection fraction and velocity of circumferential ﬁber obvious and do not require any additional comment. The trend

Journal of Human Hypertension (2015) 610 – 617 © 2015 Macmillan Publishers Limited Sex and hemodynamics in hypertension P Krzesiński et al 615 (P = 0.051) to more than twofold higher prevalence of LVH among misbalance. Narkiewicz et al.5 describe this process as evolution women suggests some distinctive features of our female from high output to vasoconstrictive hypertension. subpopulation because in general population LVH is equally The protective role of female hormones results also from its distributed among sexes.23 influence on all components of renin–angiotensin system. Estrogens decrease the synthesis of renin (while increase the Sex differences in hemodynamic interrelations synthesis of angiotensinogen) and expression of AT1 receptors. At the same time, they increase the expression of AT2 receptors that The comparative analysis revealed that central hemodynamics seem to have an enhanced role in the regulation of BP in females differ significantly in men and women. We assumed that female 31 as compared with males. Males with hypertension are also more central hemodynamics depend on different interactions between sensitive to endothelin 1, the most potent human vasoconstrictor, heart and vessels than in men. The evaluation of correlations fi mostly because of the differences in ET receptor expression, con rmed our hypothesis and revealed some clinically important activation and downstream signaling.32 observations. In both subgroups, LVMI was associated with central hemodynamics. However, in women, this relation was more pronounced, Clinical implications especially for CSBP and CPP. These results may suggest stronger Arterial stiffness, including augmented CPP and AI, is supposed to 1,3,14 influence of CPP on left ventricular remodeling and explain higher increase cardiovascular risk. In premenopausal women estro- prevalence of LVH in females. gens neutralize some unfavorable features of female hemody- The most relevant differences were observed for central namics and preserve them against adverse cardiovascular events. hemodynamics and left ventricular diastolic function. Increased When this protection disappears after menopause, women are CSBP, CPP and AI revealed to significantly influence left ventricular exposed to increased sympathetic drive and vasoconstrictive filling pressure in women. On the contrary, in men, the correlation agents. It results in the abrupt change in circulating pattern of CSBP and AI was weaker, and, for CPP, not even present. Our overlapping the previous cardiovascular dysfunction. The female results agree with the observations of Shim et al.12 that evaluated advantage becomes attenuated by comorbidities and organ 158 age-matched hypertensive women and men without any damage. As a consequence, the risk of serious complications of other heart disease. They observed only in women the association AH (that is, cardiac infarct, stroke and systolic heart failure) ′ accelerates in aging women and reaches comparable level as for of CPP and AI with early diastolic mitral annular velocity (e ) and 4,13,15,33 transmitral-to-mitral annular early diastolic velocity ratio (E/e′) men of the same age. (0.38 and − 0.36, respectively; P = 0.001). Canepa et al.24 clearly Moreover, being exposed to higher and long-lasting pressure showed the significant influence of AI on left ventricular diastolic overload, women are more predisposed to develop heart failure function, independent of pulse wave velocity. Higher CSBP may with preserved ejection fraction and ischemic heart disease even without serious coronary stenosis.4,12 To maintain the SV, female increase LV pressure load during mid-to-late systole that is a 13 crucial period for the transition from LV contraction to LV heart is forced to couple with stiffer arterial system. In response to impaired vascular compliance, left ventricle becomes hyper- relaxation. Borlaug et al.25 observed that diastolic and systolic trophic, structurally and functionally stiffer. These changes cause tissue velocities decrease with increasing arterial afterload and an increase in myocardial oxygen consumption and a decrease in late-systolic load (augmentation index) has the greatest influence myocardial perfusion pressure, which may induce imbalance in on e′. These findings may partly explain the relations of increased the supply–demand ratio and lower exercise reserve of coronary AI and CPP with increased left ventricular filling pressure revealed blood flow.12 Demonstrating low TAC and high PP, women may in our study. present limited ability to tolerate steeper rise of dynamic aortic Genetic studies provide molecular baseline to sex differences in 6 26 stiffness during exercise. the remodeling of LV exposed to pressure overload. Witt et al. Sex differences in central hemodynamics imply heterogeneous provoked LVH in mice and observed that female hearts responded response to pharmacotherapy. Women are underrepresented in with higher expression of mitochondrial genes while male ones large clinical trials and the specific sex analysis are performed with genes responsible for protein and extracellular matrix 1,13 34 27 rarely. The large meta-analysis revealed that the reduction of synthesis. Weinberg et al. reported better LV contractile reserve cardiovascular risk do not depend on either sex or antihyperten- in female hypertrophic rats related to maintained synthesis of sive drug classes but on lowering BP. It is true, but the problem +– 2+ sarcoplasmic reticulum Na Ca ATPase mRNA, which was arises when the disproportion in effectiveness of the therapy depressed in males. occurs. The lower contribution of small resistive arteries and No relation with CPP and slight association with CDBP suggest sympathetic activity in women may be associated with limited that left ventricular afterload in men is more associated with effect of vasodilators, especially in acute stress.8 Higher arterial middle and small branches of arterial tree, and in women with and heart volume load may explain better response to large arteries. The evaluation of relations of central blood pressure diuretics.13,32,35 and impedance parameters supports this hypothesis. In females, To sum up, the main differences that we observed in women both SVR and TAC influenced CBP. In males, it was just SVR. express in: (1) higher central pulse pressure and augmentation Different impact of systemic resistance on central hemodynamics index; (2) lower large arteries (aortic) compliance; (3) relatively reflected in men as the association of SVR with AI. The relatively more distinctive performance of left ventricle as a blood pump lower constriction of peripheral arteries in premenopausal women and (4) higher influence of central hemodynamics on left is probably related to their hormonal status. Estrogens appear to ventricular remodeling and diastolic function (even in the case blunt vasoconstrictive response to adrenergic stimulation, of comparable brachial BP, HR and age). increase the release of relaxing factors from endothelium The questions that should be explained in the future studies (especially nitric oxide) and protect connective tissue include: (1) the usefulness of central blood pressure in the remodeling.4,7,13,28,29 The paradox of autonomic control in women diagnosis of hypertension in normotensive women; (2) the extent expresses in higher sympathetic nerve activity but its attenuated of functional component in total arterial stiffness (that we suspect transfer to peripheral vessels. The administration of estrogens to be dominating, especially in young and middle-aged women); influences baroreflex sensitivity and sympathetic flow limiting the (3) the meaning of menopausal hormonal shift for central effect of vasoconstrictors such as norepinephrine.30 The lack of hemodynamic changes (we suppose the turn to the male female hormones after menopause results in autonomic hemodynamic pattern); (4) the influence of pharmacotherapy on

© 2015 Macmillan Publishers Limited Journal of Human Hypertension (2015) 610 – 617 Sex and hemodynamics in hypertension P Krzesiński et al 616 central hemodynamics in view of sex differences and cardiovas- 7 Hart EC, Charkoudian N, Wallin BG, Curry TB, Eisenach JH, Joyner MJ. Sex cular outcome. differences in sympathetic neural-hemodynamic balance: implications for human The main limitation of our study is that we did not measure the blood pressure regulation. Hypertension 2009; 53(3): 571–576. individual blood estrogens and progesterone levels. That limited 8 Christou DD, Jones PP, Jordan J, Diedrich A, Robertson D, Seals DR. Women have lower tonic autonomic support of arterial blood pressure the evidence for estrogen-mediated effects on the vasculature as fl 111 the major explanation for our results. Second, we did not compare and less effective barore ex buffering than men. Circulation 2005; (4): 494–498. pre- and postmenopausal women because of small subgroups 9 Lang RM, Bierig M, Devereux RB, Flachskampf FA, Foster E, Pellikka PA et al. number (29 and 16, respectively). Our results refer to the specific Recommendations for chamber quantification. Eur J Echocardiogr 2006; 7(2): population of hypertensive patients—without other cardiovascu- 79–108. lar disease, mostly young and middle-aged. Thus, the extrapola- 10 Nagueh SF, Appleton CP, Gillebert TC, Marino PN, Oh JK, Smiseth OA et al. tion of these observations on general population should be Recommendations for the evaluation of left ventricular diastolic function by carefully considered. echocardiography. Eur J Echocardiogr 2009; 10(2): 165–193. 11 Pauca AL, O’Rourke MF, Kon ND. Prospective evaluation of a method for esti- mating ascending aortic pressure from the radial artery pressure waveform. CONCLUSIONS Hypertension 2001; 38:932–937. 12 Shim CY, Park S, Choi D, Yang WI, Cho IJ, Choi EY et al. Sex differences in central The presented results show that cardiovascular function and hemodynamics and their relationship to left ventricular diastolic function. JAm pathophysiology of central hemodynamics differ between males Coll Cardiol 2011; 57(10): 1226–1233. and females. Hypertensive women characterized with lower large 13 Doumas M, Papademetriou V, Faselis C, Kokkinos P. Gender differences in artery compliance and more pronounced augmentation of central hypertension: myths and reality. Curr Hypertens Rep 2013; 15(4): 321–330. blood pressure by both forward and reflected waves. In addition, 14 Smulyan H, Asmar RG, Rudnicki A, London GM, Safar ME. Comparative effects of females characterized with more distinctive association of central aging in men and women on the properties of the arterial tree. J Am Coll Cardiol blood pressure with left ventricular filling pressure. Our observa- 2001; 37(5): 1374–1380. tions revealed sex differences in cardiovascular function that can 15 Berry KL, Cameron JD, Dart AM, Dewar EM, Gatzka CD, Jennings GL et al. Large- artery stiffness contributes to the greater prevalence of systolic hypertension in impact the approach to the individualized management of arterial elderly women. J Am Geriatr Soc 2004; 52(3): 368–373. hypertension. 16 Segers P, Rietzschel ER, De Buyzere ML, Vermeersch SJ, De Bacquer D, Van Bortel LM et al. Noninvasive (input) impedance, pulse wave velocity, and wave reflection in healthy middle-aged men and women. Hypertension 2007; What is known about the topic 49(6): 1248–1255. ● The knowledge about sex differences in cardiovascular function in 17 McKinney ME, Buell JC, Eliot RS. Sex differences in transthoracic impedance: arterial hypertension is still deficient. evaluation of effects on calculated stroke volume index. Aviat Space Environ Med 1984; 55(10): 893–895. 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